Neuroscience
Month
August 2, 2012
New tools have confirmed high rates of misdiagnosis of patients with chronic disorders of consciousness, such as the vegetative state. An increasing number of patients’ families wish to use these novel techniques for diagnosis, prognosis, and treatment. An international team of researchers, including Dr. Éric Racine, researcher at the IRCM, analyzed the clinical, social and ethical issues that clinicians are now facing. Their article is published in the August edition of The Lancet Neurology, a renowned journal in the field of clinical neurology.
"Patients with disorders of consciousness have traditionally been regarded as unaware by definition, but findings from recent clinical studies have revealed astounding cases of awareness despite clinical unresponsiveness," explains Dr. Racine, a Montréal neuroethics specialist.
Severe brain injury can leave patients with chronic disorders of consciousness, which are medical conditions that inhibit consciousness. Patients thus have severe motor and cognitive impairments, remain fully dependent on others for all activities of daily living, and have no or very limited means to functionally communicate their thoughts or wishes, depending on their state.
Even with a careful neurological assessment of these types of disorders, some signs of awareness can elude the clinician because the clinical diagnosis relies on the observation of motor signs of awareness, which can be very subtle and fluctuate over time.
New technological developments can now measure brain function both in resting states and in response to simple commands, independent of muscle function, which could help establish a more accurate diagnosis. As a result, diagnostic classifications have been revised and prognostic knowledge is improving. For the first time, therapeutic studies have recently shown the effects of treatment on the improvement of patient responsiveness.
"The medical decision to stop or continue rehabilitation, or to transfer a patient to a long-term care facility can be hard to accept for the family, but one of the most difficult treatment decisions by family members remains whether to continue life-sustaining therapy or to discontinue it and only provide palliative care," says Dr. Racine.
Media coverage of disorders of consciousness has increased and information on the subject is increasingly available to the public. Clinicians such as neurologists, rehabilitation specialists, family doctors, and nurses must answer more requests from patients’ family members for novel diagnostic and therapeutic procedures.
"Clinicians therefore need to be prepared to discuss disorders of consciousness with ethical sensitivity, especially considering that the new procedures remain investigational," adds Dr. Racine. "They must be aware of the level of evidence supporting them and of the unavoidable ethical and social issues involved in responding to requests from patients’ family members."
Provided by Institut de recherches cliniques de Montreal
Source: medicalxpress.com
Have you ever gone on a trip and unexpectedly found yourself in need of medical care? What if your condition could have been predicted? Better yet, what if you already had the medicine needed to treat that condition in your luggage?
The Hierarchical Association Rule Model (HARM), which I co-developed with Tyler McCormick of the University of Washington and David Madigan of Columbia University, can help patients be better prepared by warning them (and their doctors) about the conditions they may likely experience next. The predictive modeling tool checks data about an individual patient against other patients in the database with similar situations to help determine future conditions. It also alerts patients about any higher risks they may have for certain types of conditions.
ScienceDaily (Aug. 1, 2012) — Scientists have known for some time that throwing off the body’s circadian rhythm can negatively affect body chemistry. In fact, workers whose sleep-wake cycles are disrupted by night shifts are more susceptible to chronic inflammatory diseases such as diabetes, obesity and cancer.
Researchers at the Salk Institute for Biological Studies have now found a possible molecular link between circadian rhythm disturbances and an increased inflammatory response. In a study published July 9 in Proceedings of the National Academy of Sciences, the Salk team found that the absence of a key circadian clock component called cryptochrome (CRY) leads to the activation of a signaling system that elevates levels of inflammatory molecules in the body.
"There is compelling evidence that low-grade, constant inflammation could be the underlying cause of chronic diseases such as diabetes, obesity and cancer," says senior author Inder Verma, a professor in Salk’s Laboratory of Genetics and the Irwin and Joan Jacobs Chair in Exemplary Life Science. "Our results strongly indicate that an arrhythmic clock system, induced by the absence of CRY proteins, alone is sufficient to increase the stress level of cells, leading to the constant expression of inflammatory proteins and causing low-grade, chronic inflammation."
Cryptochrome serves as a break to slow the circadian clock’s activity, signaling our biological systems to wind down each evening. In the morning, CRY stops inhibiting the clock’s activity, helping our physiology ramp up for the coming day.
To gain insight into the role of circadian clock components on immune function, the Salk scientists measured the expression of inflammatory mediators in the hypothalamus (the area of the brain responsible for sleep-wake cycle regulation) of mice with deleted CRY genes. Through a variety of tests, these knockout mice showed a significant increase in the expression of certain inflammatory proteins known as cytokines, including interleukin-6 and tumor necrosis factor-α, compared to mice with CRY genes.
"Our findings demonstrate that a lack of cryptochrome activates these proinflammatory molecules, indicating a potential role for cryptochrome in the regulation of inflammatory cytokine expression," says Satchidananda Panda, an associate professor in Salk’s Regulatory Biology Laboratory and one of the senior authors of the study.
In addition, the researchers found that a lack of CRY activated the NF-kB pathway, a molecular signaling conduit that controls many genes involved in inflammation. NF-kB is a protein complex in a cell’s cytoplasm, “just happily doing nothing,” says Verma. In response to stimuli, it is transferred to the cell’s nucleus, where it binds to inflammation genes and turns them on. The regulation of these genes is tightly controlled, but NF-kB does not completely shut off their expression. This lingering expression causes inflammation.
"Every time this pathway is turned on, there is a residual amount of inflammation left in the body," says Rajesh Narasimamurthy, a research associate in Verma’s laboratory and the paper’s first author. "That adds up over time, contributing to inflammation-related diseases like obesity and diabetes."
Previous research has shown that suppressing the activity of the NF-kB pathway might be a suitable therapy for some diseases. For example, NF-kB is activated automatically in cancer cells of multiple myeloma, which affects infection-fighting plasma cells in the bone marrow and allows the cells to proliferate. Drugs that inhibit this activity might be able to degrade NF-kB to the point that it may kill off the disease.
The researchers say the goal now is to find out how to suppress NF-kB activation in the short term to treat diseases like diabetes. They caution that any long-term suppression of the pathway could lead to chronic infection. “We would like to find molecules that modify this activity and focus on those small-molecule inhibitors to treat disease,” Verma adds.
Source: Science Daily
August 1, 2012
(Medical Xpress) — In work that may revolutionise rehabilitation for stroke patients, researchers from The University of Auckland and the Auckland District Health Board have shown it is possible to predict an individual’s potential for recovery of hand and arm function after a stroke.
The new approach can be used to personalise rehabilitation so that patients and therapists set realistic goals for recovery. It may also improve outcomes of trials that evaluate new therapies, by identifying patients who are most likely to respond to specific treatments.
“One in six people worldwide will have a stroke in their lifetime,” says principal investigator Professor Winston Byblow. “After stroke, impairment of the arm and hand is very common and has a major impact on independence and quality of life.
“Until now it has only been possible to group patients together according to their broad similarity to others who have already gone through upper limb rehabilitation, but this information cannot inform an individual patient’s rehabilitation plan. We have developed the first clinical algorithm to actually predict the individual patient’s potential for recovery based on information gathered before rehabilitation begins.”
The lead author of the study, Dr Cathy Stinear explains: “The algorithm begins with a bedside test within three days of stroke. The test takes only a few minutes and requires no special equipment. This is sufficient to provide a prediction for many patients, but for others an additional test is required to measure the integrity of neural pathways from the brain to the arm. If this test gives no definitive result, an MRI assessment can be performed to better determine whether the pathways in the stroke-damaged side of the brain remain viable.”
The research team have trialled the process in patients and followed their recovery. “When the tests are combined in our stepwise algorithm they accurately predict each patient’s recovery at 12 weeks, which is around the time that therapy normally ends,” says Dr Stinear.
Neurologist Professor Alan Barber, a member of the research team and Head of the Auckland Hospital Stroke Service, says that the findings are very significant. “This is the first study to predict an individual’s potential for motor recovery using measures obtained from that patient in the initial days after stroke. This information can be used to tailor rehabilitation before it begins.”
The team is now involved in a three-year trial of the algorithm within the hospital. The results will show whether the algorithm leads to improved outcomes for patients and increases the efficiency of rehabilitation services.
Provided by University of Auckland
Source: medicalxpress.com
ScienceDaily (July 31, 2012) — Research just published by scientists at Cold Spring Harbor Laboratory (CSHL) links gene mutations found in some patients with Meier-Gorlin syndrome (MGS) with specific cellular dysfunctions that are thought to give rise to a particularly extreme version of dwarfism, small brain size, and other manifestations of abnormal growth which generally characterize that rare condition.
Although only 53 cases of Meier-Gorlin syndrome have been reported in the medical literature since the first patient was described in 1959, it is a malady whose mechanisms are bringing to light new functions for some of the cellular processes common to all life. Pathology related to MGS is traced in the new research to one of these, the fundamental process called mitosis in which cells replicate their genetic material and prepare to divide into two identical “daughter” cells.
CSHL President and Professor Bruce Stillman, Ph.D., a cancer biologist who has made seminal discoveries over three decades that have helped reveal the exquisite choreography of how chromosomes are duplicated in cells, led the new research, which suggests how, during mitosis, mutant versions of a protein called Orc1 contribute in two distinct ways to severe MGS pathology. The research is published online ahead of print in Genes & Development.
ScienceDaily (July 31, 2012) — New research demonstrates that blocking the delta opioid receptor in mice created resistance to weight gain and stimulated gene expression promoting non-shivering thermogenesis.
Imagine eating all of the sugar and fat that you want without gaining a pound. Thanks to new research published in The FASEB Journal, the day may come when this is not too far from reality. That’s because researchers from the United States and Europe have found that blocking one of three opioid receptors in your body could turn your penchant for sweets and fried treats into a weight loss strategy that actually works. By blocking the delta opioid receptor, or DOR, mice reduced their body weight despite being fed a diet high in fat and sugar. The scientists believe that the deletion of the DOR gene in mice stimulated the expression of other genes in brown adipose tissue that promoted thermogenesis.
"Our study provided further evidence that opioid receptors can control the metabolic response to diets high in fat and sugar, and raise the possibility that these gene products (or their respective pathways) can be targeted specifically to treat excess weight and obesity," said Traci A. Czyzyk, Ph.D., a researcher involved in the work from the Department of Physiology at the Mayo Clinic in Scottsdale, Arizona.
Scientists studied mice lacking the delta opioid receptor (DOR KO) and wild type (WT) control mice who were fed an energy dense diet (HED), high in fat and sugar, for three months. They found that DOR KO mice had a lean phenotype specifically when they were fed the HED. While WT mice gained significant weight and fat mass on this diet, DOR KO mice remained lean even though they consumed more food. Researchers then sought to determine how DOR might regulate energy balance and found that DOR KO mice were able to maintain their energy expenditure levels, in part, due to an increase in non-shivering thermogenesis. This was evidenced by an increase in thermogenesis-promoting genes in brown adipose tissue, an increase in body surface temperature near major brown adipose tissue depots, and the ability of DOR KO mice to maintain higher core body temperatures in response to being in a cold environment.
"Don’t reach for the ice cream and doughnuts just yet," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. “We don’t know how all this works in humans, and of course, a diet of junk food causes other health problems. This exciting research identifies genes that activate brown adipose tissue to increase our burning of calories from any source. It may lead to a safe diet pill in the future.”
Source: Science Daily
July 31, 2012
Wayne State University School of Medicine researchers, working with colleagues in Canada, have found that one or more substances produced by a type of immune cell in people with multiple sclerosis (MS) may play a role in the disease’s progression. The finding could lead to new targeted therapies for MS treatment.
B cells, said Robert Lisak, M.D., professor of neurology at Wayne State and lead author of the study, are a subset of lymphocytes (a type of circulating white blood cell) that mature to become plasma cells and produce immunoglobulins, proteins that serve as antibodies. The B cells appear to have other functions, including helping to regulate other lymphocytes, particularly T cells, and helping maintain normal immune function when healthy.
In patients with MS, the B cells appear to attack the brain and spinal cord, possibly because there are substances produced in the nervous system and the meninges — the covering of the brain and spinal cord — that attract them. Once within the meninges or central nervous system, Lisak said, the activated B cells secrete one or more substances that do not seem to be immunoglobulins but that damage oligodendrocytes, the cells that produce a protective substance called myelin.
The B cells appear to be more active in patients with MS, which may explain why they produce these toxic substances and, in part, why they are attracted to the meninges and the nervous system.
The brain, for the most part, can be divided into gray and white areas. Neurons are located in the gray area, and the white parts are where neurons send their axons — similar to electrical cables carrying messages — to communicate with other neurons and bring messages from the brain to the muscles. The white parts of the brain are white because oligodendrocytes make myelin, a cholesterol-rich membrane that coats the axons. The myelin’s function is to insulate the axons, akin to the plastic coating on an electrical cable. In addition, the myelin speeds communication along axons and makes that communication more reliable. When the myelin coating is attacked and degraded, impulses — messages from the brain to other parts of the body — can “leak” and be derailed from their target. Oligodendrocytes also seem to engage in other activities important to nerve cells and their axons.
The researchers took B cells from the blood of seven patients with relapsing-remitting MS and from four healthy patients. They grew the cells in a medium, and after removing the cells from the culture collected material produced by the cells. After adding the material produced by the B cells, including the cells that produce myelin, to the brain cells of animal models, the scientists found significantly more oligodendrocytes from the MS group died when compared to material produced by the B cells from the healthy control group. The team also found differences in other brain cells that interact with oligodendrocytes in the brain.
"We think this is a very significant finding, particularly for the damage to the cerebral cortex seen in patients with MS, because those areas seem to be damaged by material spreading into the brain from the meninges, which are rich in B cells adjacent to the areas of brain damage," Lisak said.
The team is now applying for grants from several sources to conduct further studies to identify the toxic factor or factors produced by B cells responsible for killing oligodendrocytes. Identification of the substance could lead to new therapeutic methods that could switch off the oligodendrocyte-killing capabilities of B cells, which, in turn, would help protect myelin from attacks.
Provided by Wayne State University
Source: medicalxpress.com
July 31, 2012
(HealthDay) — For patients with dementia with Lewy bodies (DLB), treatment with 5 or 10 mg/day donepezil is associated with significant cognitive, behavioral, and global function improvements, according to research published in the July issue of the Annals of Neurology.
Etsuro Mori, M.D., Ph.D., of the Tohoku University Graduate School of Medicine in Sendai, Japan, and colleagues conducted a randomized, double-blind, placebo-controlled trial involving 140 patients with DLB who received either placebo or 3, 5, or 10 mg of donepezil hydrochloride per day for 12 weeks (35, 35, 33, and 37 patients, respectively). Cognitive function was measured using the Mini-Mental State Examination (MMSE); behavioral changes were measured using the Neuropsychiatric Inventory; global function was evaluated using the Clinician’s Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus); and caregiver burden was also assessed.
The researchers found that, compared with placebo treatment, the MMSE scores were significantly better with donepezil 5 mg (mean difference, 3.8) and 10 mg (mean difference, 2.4), but the 3 mg/day dose was not significantly better than placebo (P = 0.017). Donepezil at doses of 3, 5, and 10 mg/day correlated with significant improvements versus placebo on CIBIC-plus. Both the 5 and 10 mg doses of donepezil resulted in significant improvements in behavioral measures. Caregiver burden also improved, but only with the 10 mg/day dose. The safety results were similar among the groups and were consistent with the known profile.
"Donepezil at 5 and 10 mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose," the authors write. Several authors disclosed financial ties to pharmaceutical companies, including Eisai Co., which funded the study and manufactures donepezil.
Source: medicalxpress.com
Jul 31, 2012 by Laura Bailey
Concussions and even lesser head impacts may speed up the brain’s natural aging process by causing signaling pathways in the brain to break down more quickly than they would in someone who has never suffered a brain injury or concussion.
The photos compare images of two brains, one with and without head injury. The red areas indicates electrical activity in response to the task researchers asked study participants to perform, and non-injured brains show more red, thus more electrical activity during the task. Image courtesy of Steven Broglio
Researchers from the University of Michigan School of Kinesiology and the U-M Health System looked at college students with and without a history of concussion and found changes in gait, balance and in the brain’s electrical activity, specifically attention and impulse control, said Steven Broglio, assistant professor of kinesiology and director of the Neurotrauma Research Laboratory.
The declines were present in the brain injury group up to six years after injury, though the differences between the study groups were very subtle, and outwardly all of the participants looked and acted the same.
Broglio, who is also affiliated with Michigan NeuroSport, stressed that the studies lay out a hypothesis where concussions and head impacts accelerate the brain’s natural aging process.
The study, “Cognitive decline and aging: The role of concussive and subconcussive impacts,” appears in the July issue of journal Exercise and Sport Sciences Reviews.
"The last thing we want is for people to panic. Just because you’ve had a concussion does not mean your brain will age more quickly or you’ll get Alzheimer’s," Broglio said. "We are only proposing how being hit in the head may lead to these other conditions, but we don’t know how it all goes together just yet."
Broglio stressed that other factors, such as lifestyle choices, smoking, alcohol consumption, physical exercise, family history and whether or not you “exercise” your brain also impact the brain’s aging process. Concussion may only be one small factor.
To begin to understand how concussions might impact brain activity and its signaling pathways, researchers asked the participants to perform certain tasks in front of a computer, and took images of their brains. The brains of the nonconcussed group showed a greater area of electrical activation than the participants with a history of brain injury.
The signaling pathways in our brains are analogous to a five-lane highway. On a new highway, traffic runs smoothly and quickly as all lanes are in top shape. However, during normal aging, the asphalt deteriorates and lanes might become bumpy or even unusable. Traffic slows.
Similarly, our brains start with all pathways clear to transfer electrical signals rapidly. As we age, the brain’s pathways break down and can’t transfer the information as quickly. Concussive and other impacts to the head may result in a ‘pothole’ on the brain’s highway, causing varying degrees of damage and speeding the pathway’s natural deterioration.
"What we don’t know is if you had a single concussion in high school, does that mean you will get dementia at age 50?" Broglio said. "Clinically, we don’t see that. What we think is it will be a dose response.
"So, if you played soccer and sustained some head impacts and maybe one concussion, then you may have a little risk. If you went on and played in college and took more head balls and sustained two more concussions, you’re probably at a little bigger risk. Then if you play professionally for a few years, and take more hits to the head, you increase the risk even more. We believe it’s a cumulative effect."
In the next phase of study, researchers will look at people in their 20s, 40s and 60s who did and did not sustain concussions during high school sports. They hope to learn if there is an increasing effect of concussion as the study subjects age. If interested in participating in the study, email neurotraumalab.umich@gmail.com.
Researchers from the departments of Physical Medicine and Rehabilitation, and Neurology, and the Michigan Alzheimer’s Disease Center also participated in the study.
Source: University of Michigan
July 31, 2012
The presence of specific autoantibodies of the immune system is associated with blood vessel damage in the brain. These findings were made by Marion Bimmler, a graduate engineer of medical laboratory diagnostics at the Max Delbrück Center for Molecular Medicine Berlin-Buch and Dr. Peter Karczewski of the biotech company E.R.D.E.-AAK-Diagnostik GmbH in studies on a rat model. The researchers’ results suggest that autoimmune mechanisms play a significant role in the pathogenesis and progression of Alzheimer’s and vascular dementia.
(MR Angiography/Copyright: MDC)
Antibodies are the defense molecules of the body’s immune system against foreign invaders. If the antibodies cease to distinguish between “foreign” and “self”, they attack the cells of the own body, and are thus referred to as autoantibodies. These can trigger autoimmune diseases. Using MR angiography and other methods, Marion Bimmler and her colleagues have now shown that the autoantibodies bind to specific surface proteins (alpha1 andrenergic receptors) of vascular cells and thereby damage the blood vessels of the brain. The reason: The autoantibodies generate a continual stimulation of the receptor and at the same time trigger an increase in intracellular calcium ion levels. As a result, the blood vessel walls thicken, and blood flow to the brain is disturbed.
First Encouraging Results after Removal of Autoantibodies by Immunoadsorption
In earlier studies, Marion Bimmler and her research team examined blood samples of patients with Alzheimer’s or vascular dementia and showed that half of them had comparable autoantibodies. A first clinical trial together with Charité – Universitätsmedizin Berlin is currently ongoing with a collective of patients with Alzheimer’s or vascular dementia. The patients were divided into two groups – a small group whose autoantibodies were removed from the blood via immunoadsorption and a control group that did not receive this treatment. Until now, over an observation period of 6 and subsequently 12 months, the patient group who had undergone immunoadsorption improved in their memory performance and in their ability to cope with their everyday lives. In contrast, the condition of the patients who did not receive immunoadsorption treatment and continued to have autoantibodies in their blood deteriorated dramatically. Now the researchers are planning further clinical trials with larger numbers of patients.
Provided by Helmholtz Association of German Research Centres
Source: medicalxpress.com